This project began with compelling theoretical evidence and intriguing empirical hints to support our innovative hypothesis that schizophrenia (SZ) is associated with learning and temporal processing deficits linked to dysfunction of the cerebellum (CB) and related circuits. In the intervening years we found striking empirical evidence in SZ of behavioral dysfunction on several CB-dependent tasks, including associative learning (eyeblink conditioning), motor timing (finger tapping), and time perception (temporal bisection). Moreover, we found that 1st-degree relatives of SZ patients and individuals with schizotypal personality disorder also exhibit associative learning deficits. Finally, correlations between performance on CB-dependant tasks and cognitive functioning support contemporary models of the role of the CB in cognition. Taken together, our findings of learning and temporal processing deficits dovetail elegantly with emerging evidence of structural and functional CB abnormalities in SZ, and warrant further investigation for several important reasons. First, we must determine whether the observed behavioral deficits are associated with direct evidence of functional and structural CB abnormalities. We will use fMRI to investigate whether task-related CB activation predicts behavioral performance deficits in SZ across three tasks: eyeblink conditioning, finger tapping, and temporal bisection. Second, it is critical to determine whether SZ is associated with impaired cortico-CB connectivity. We will use MRI to examine resting-state functional connectivity and DTI-based structural connectivity between the CB and select cerebral regions that normally have strong neuroanatomical connections with the CB-though it is not known if this is the case in SZ-and are thought to be involved in temporal processing. Task-related fMRI dynamic causal modeling will be used to study directional influences between brain regions. Third, it is critical to understand whether neuroimaging dependent variables predict cognitive performance, so we have selected a battery of tasks with strong evidence of CB involvement. Fourth, our preliminary evidence that CB-dependent eyeblink conditioning is impaired in 1st-degree relatives of SZ patients and in schizotypal personality disorder begs the question of whether CB abnormalities represent endophenotypes of SZ. Forty individuals with SZ and 40 of their 1st-degree relatives will complete a battery of tasks to address these questions. Their performance will be compared to age- and sex-matched non-psychiatric control subjects (N=80). Successfully completing the proposed research will determine: (1) whether CB dysfunction underlies behavioral abnormalities observed in SZ on associative learning and temporal processing tasks; and (2) whether CB abnormalities represent endophenotypes of SZ. Our data will critically inform models of CB involvement in cortical cognitive processing in psychiatric illness and yield insights about potential novel mechanisms of illness and targets of treatment. PUBLIC HEALTH RELEVANCE: This study will lead to improved understanding of the neural mechanisms underlying schizophrenia, which is an extraordinarily debilitating psychological disorder. The resulting knowledge will be especially informative about the role of an understudied region of the human brain called the cerebellum, and may lead to the identification and development of innovative treatments.